The Neurodevelopmental Hypothesis of Schizophrenia

Clare Holtam

Schizophrenia is a term used to describe a group of mental illnesses which are
diverse in nature and cover a broad range of cognitive, emotional and behavioural
disturbances.

It is a common disorder with up to 600,000 sufferers in the UK. The incidence and
prevalence rates are considered to be consistent World wide at 0.15-0.20 per 1000
per year and 2-4 per 1000 per year, respectively. The lifetime risk of schizophrenia
in the general population is about 1% but for first-degree relatives of sufferers this is
increased to 10%. (1)

Core features of schizophrenia include: auditory hallucinations, particularly in the
third person; changes in thought construction and form; and bizarre delusions in
which, for example, the patient believes their thoughts to be available to others or
that they are influenced by outside forces. These positive psychotic phenomena
comprise the key diagnostic features, and usually occur together with changes in an
individual's behaviour or social functioning. In addition, there may be negative
features, such as restriction of the range of emotions (blunting of affect) and
decreased ability to initiate thoughts and ideas (poverty of thought).

Currently, operational criterion-based systems are used to diagnose schizophrenia;
examples of such systems include the International Classification of Diseases, tenth
edition (ICD-10) (1) and the Diagnostic and Statistical Manual of Mental Disorders,
fourth edition (DSM-IV). (2)

Schizophrenia is divided into a number of subtypes, although many patients present
with symptoms and behaviours belonging to more than one category. The most
common subtype of schizophrenia currently found in the UK is paranoid
schizophrenia which has a later age of onset and a more insidious course than the
others.

Schizophrenia has a dramatic influence on the lives of sufferers and their families
often striking in early adult life just when individuals would be experiencing most
independence and starting a productive career. In addition to the social and
psychological anguish it causes schizophrenia creates a huge economic burden for
society. In the UK 5.4% of the total National Health Service inpatient costs are
attributable to schizophrenia. When inpatient, outpatient, primary care,
pharmaceutical, community and social services expenses are combined the total cost to the UK of
2.6 billion per year is estimated. (4)

The cause of schizophrenia is unknown. During this century various theories have
been proposed to ranging from social and psychological ideas to biological, genetic
and environmental hypotheses. A brief overview some of these theories is presented
below.

In 1948 Fromm-Reichmann suggested a 'schizophrenogenic' mother, one who is
both overprotective and hostile to her children, caused schizophrenia. Lidz proposed
the disorder was the consequence of 'marital skew 'and' marital schism. (5, 6)
Marital skew describes the situation where one parent dominates the other. Marital
schism is when parents have contrary views which are thought to cause a child to
have divided loyalties. However, subsequent studies failed to confirm such ideas (7,
8) and it is suggested the findings were the result, as opposed to the cause of
schizophrenia. Disorders of communication within families have also been
suggested to be of aetiological significance. (9, 10)

Life events have been proposed to be a cause of schizophrenia. This suggestion is
based on the finding that schizophrenics experience significantly more life events in
the three weeks prior to the onset of the illness and that life events appear to
precipitate relapses. (11-15)

Biochemical theories of schizophrenia include the dopamine and glutamate
hypotheses. (16) The dopamine hypothesis was based on the pharmacological
findings that the drugs stimulating central dopamine receptors, can produce a
disorder indistinguishable from schizophrenia; and that anti-psychotic drugs block
dopamine receptors. All the new information produced by studies into
schizophrenia, however, cannot be accounted for simply by abnormalities with
dopamine.

Family, twin, adoption and epidemiological studies provide considerable evidence
for the genetic contribution to the aetiology of schizophrenia. (1) However, despite
numerous linkage and association studies with candidate genes for schizophrenia no
one gene for schizophrenia has been found and results have largely been negative or
inconsistent. (17) The possibility that schizophrenia is a single gene disorder has
been excluded (18) and transmission is now thought to involve multiple susceptible
loci. (1)

Although twin studies provide compelling evidence for genetics in the causation of
schizophrenia they also establish the importance of environmental influences. The
findings that both affected and unaffected monozygotic twins pass the same
increased risk of development of schizophrenia to their children; (19, 20) and in
monozygotic twins discordant for schizophrenia the affected twin has larger
ventricles and less temporal lobe grey matter than the unaffected twin (21, 22)
suggests the involvement of more than just genetics in the aetiology of the disorder.
The environmental factors implicated in the aetiology of schizophrenia are discussed
in the following section.

The neurodevelopmental hypothesis of schizophrenia proposes that a proportion of
schizophrenia is the result of an early brain insult, either pre or perinatal, which
affects brain development leading to abnormalities which are expressed in the mature
brain. (23-26) This idea is not new, Kraeplin and others throughout the 20th century
argued that some cases of schizophrenia probably resulted from insults that cause
cerebral maldevelopment. (27, 28) The cause of the brain lesion is postulated to be
either from the inheritance of abnormal genes, which impair brain development, or
from some fetal or neonatal adversity.

The following section discusses the strength of the neuropathological, clinical and
epidemiological findings evidence in support of the neurodevelopmental hypothesis.
Firstly, reports of neuropathology will be evaluated followed by data from studies of
premorbid children with abnormalities which are interpreted to represent cerebral
maldevelopment. The third section reviews studies that have attributed the cerebral
abnormalities to specific aetiological factors. Finally, there will be a discussion of
the mechanisms proposed to explain how and why the onset of the illness is delayed
until 20-30 years after the initial insult.

Post-mortem and brain imaging studies into schizophrenia have shown the disorder
to be associated with disturbances in cerebral structure. However, researchers have
reported different brain regions to be affected to varying extents. A meta-analysis of
40 MRI studies (29) described the following abnormalities in the brains of
schizophrenics:

Volume reductions:

Whole Brain (3%)

Temporal lobe (left 6% right 9.5%)

Amygdala/hippocampal complex (left 6.5%, right 5.5%)

Volume is increased in the lateral ventricles (left 44%, right 36%)

Grey matter is reduced but white matter volumes may be increased

These brain abnormalities are thought to be neurodevelopmental in origin, as
opposed to neurodegenerative, because of reports they are found in newly diagnosed
patients as well as chronic schizophrenics, (30-35) and as they appear to be non-
progressive. (36-41) Also, it is argued that if the disease process of schizophrenia
were progressive then so would be the neuropsychological profile; but the cognitive
deficits found in schizophrenia show no deterioration over the course of the illness.
(42) However, reports of changing brain volumes in schizophrenia are inconsistent
(43), and since 1989 there have been both positive (44-46) and negative (47, 48)
longitudinal computed tomography findings of progressive volume loss in
schizophrenia; and both positive (49-51) and negative (38, 52) longitudinal magnetic
resonance imaging results in follow-up investigations of first episode schizophrenia.
In addition, there is evidence for progressive ventricular enlargement in childhood-
onset schizophrenia. (53) Moreover, the failure to find conclusive evidence of brain
volume loss over time is not proof that neuronal degeneration does not occur in
schizophrenia unless it is assumed that there is a temporal relationship between
degeneration and symptomatic illness.

Many imaging studies also report the presence of excessive extracerebral CSF in
schizophrenia. (54-55) This is difficult to explain using a model of an early static
defect in brain development as brain volume triples between birth and the age of five
years and any increase in extracerebral volume would tend to be filled up by the
outward growth of the brain.

Nevertheless, compelling evidence in support of the neurodevelopmental hypothesis
comes from studies of cortical cytoarchitecture which discovered neurons in
schizophrenic brains to be misplaced, mis-sized and disorganised. (56-59) Such
findings are difficult to explain in any other than neurodevelopmental terms as they
are suggestive of impaired neuronal migration which takes place during the second
trimester of pregnancy. However the findings remain controversial. (60)

Gliosis is the neural scarring which accompanies brain lesions other than those which
occur during early development and is regarded as a characteristic feature of
neuronal degeneration. In schizophrenic brains the balance of neuropathological
evidence is strongly against excessive gliosis being characteristic of schizophrenia.
(61-68) Also, there is no evidence of increased glial membrane turnover signals in
magnetic resonance spectroscopy in either chronic schizophrenia or at the time of
disease onset. (69) This is supportive of the idea that the damage to the brain in
schizophrenia occurs early in life and is not due to a neurodegenerative process.
However, earlier studies of schizophrenic brains did report gliosis, (70) although this
could be explained by technical issues; with results being dependent on specific
staining procedures (71) or vulnerability to long fixation times. (72) In addition,
some researchers report that the brain can respond to injury with gliosis as early as
the 20th week of gestation (73) and certainly throughout the third trimester (74)
suggesting that any perinatal brain injury should result in gliosis.

In schizophrenia there is a failure to develop normal cerebral asymmetries. (75-80)
Since normal human brain asymmetries are formed early in development, during the
second trimester of gestation, these findings suggest the occurrence a pathological
event interfering with this stage of development. However, such findings remain
controversial and are only suggestive, not conclusive, of deviant neurodevelopment.
(81-83)

In some studies, pathological changes appear to affect the left side of the brain more
severely than the right. (20, 60, 76, 84, 85) This is potentially explicable in
neurodevelopmental terms as the left hemisphere of the brain is thought to develop
more slowly than the right hemisphere during early to mid gestation and so could be
more vulnerable to injury or vulnerable for a longer period of time.

Further evidence in support of the neurodevelopmental hypothesis is the aberrant
expression of developmental and plasticity associated markers such as the embryonic
isoform of the neural adhesion molecule (NCAM) (86) and the growth-associated
protein 43 (GAP-43) (87) in the brains of schizophrenics.

Finally, sulcal-gyral abnormalities have been reported in some post-mortem studies
of schizophrenic brains. (88, 89) Since gyrification in the human brain is largely
intrauterine between weeks 16 and 29 (90) such abnormalities are highly suggestive
of a process affecting the fetal brain at this stage of development. However, these
studies were not conducted blind and may not have accounted sufficiently for the sex
differences in the sulcal-gyral pattern. (91) Nevertheless, the findings have since
been confirmed in a later study (92)

If schizophrenia is caused by an aberration in the developing brain then it is
reasonable to expect some subtle abnormalities of neural function and developmental
anomalies to be present in early life.

Several lines of circumstantial data support this possibility. Preschizophrenic
children have a higher incidence of: neuromotor abnormalities; delayed attainment of
developmental milestones; and behavioural and intellectual abnormalities. (93-96)
They are also often described as having 'schizoid' personality traits such as being
socially withdrawn, aloof and preferring to play alone. (94, 97) One study, using old
home movie tapes, revealed that in the first two years of life children who were to
become schizophrenic had reduced responsiveness, less positive affect and less eye
contact. (98) Another study reported that children who go on to develop
schizophrenia perform less well than their contempories in tests of
neuropsychological and academic performance. (99) 75% of people who go on to
develop schizophrenia have 'soft' neurological signs as children. These include:
slightly abnormal gaits in children; dysgraphaesthesia; proprioceptive errors; tics;
twitches and epileptic attacks. (93, 94) The results of these studies, while open to
other interpretations, are consistent with the possibility of brain maldevelopment.
Nevertheless, despite all these reports, many children who go on to develop
schizophrenia have shown high levels of social, academic and occupational
functioning. So it appears there is a subgroup of schizophrenics who have been
subtly impaired for years before the onset of overt positive schizophrenic symptoms,
implying a proportion of schizophrenia is attributable to a neurodevelopmental
defect.

Schizophrenic patients are also reported to have a higher prevalence of minor
physical anomalies than the general population. (100) Dermatoglyphic asymmetry,
(101-103) and cerebral anomalies, such as agenesis of the corpus callosum and
cavum septum pellucidum, and developmental cysts, (104) are both found more
commonly in schizophrenics and are both indicative of disturbed intrauterine
development. Additionally, minor physical abnormalities including: low set ears;
furrowed tongue; high arched palate; curved fingers; greater distance between the
eyes and a single palmer crease are also found more frequently in schizophrenics,
particularly in males and in those with a positive family history. (100, 105) Both the
skin and the central nervous system are derived from the ectodermal tissue in utero,
so such visible anomalies can be considered as external markers of damage to
ectodermal structures of the fetus and as such can be interpreted as indirect support
for the occurrence of aberrant neurodevelopment. Such anomalies are also found in
other disorders of neurodevelopment such as Down's syndrome and intrauterine viral
encephalopathies. However, this theory remains controversial (106) with the true
frequency of these abnormalities in schizophrenia unknown and uncertainty as to
whether all the morphological characteristics reported are actually pathological.

If schizophrenia is a neurodevelopmental disorder the causes must act early in
development. It is feasible that genes may be involved in the genesis of the brain
abnormalities and the finding that environmental risk factors associated with
schizophrenia act pre- or perinatally offers further support for the
neurodevelopmental hypothesis. However, the presence of risk factors early in life
does not necessarily mean that schizophrenia must be developmental in an overall
sense, for example, there are early risk factors for stroke.

People who develop schizophrenia are born in winter and spring slightly more
frequently than the general population. (107) and several studies indicate that the
increased risk for winter births is enhanced among those born in large cities and is
greater the colder the winter. (108, 109) The possibility that this observed
seasonality could be a statistical artefact or merely an accentuation of the
seasonality seen in general births has generally been refuted. (110) The findings
suggest the influence of some intrauterine factor that varies seasonally.
Environmental factors proposed include infectious agents, nutritional factors, and the
temperature variations at the time of conception. Maternal infection could affect
fetal brain development through in utero infection; maternal fever; maternal
antibodies crossing the placenta and acting as fetal anti-brain antibodies; or maternal
use of analgesics. Support of infection as the cause of this phenomenon are the
reports that viral entry into the CNS is promoted by exposure to cold (111) and the
demonstration by rubella that viral infection in a pregnant women can cause
permanent damage to the fetal nervous system.

Maternal infection with the influenzae is also claimed to be associated with the later
development of schizophrenia in the unborn child, particularly in females. (112-118)
However, the existence and importance of this effect remains controversial, (119-
121) as although ecological studies show an association between schizophrenia and
the timing of the great influenzae epidemics there is yet to be a convincing
demonstration of this effect in individuals known to both have been exposed to
influenzae in utero and to have developed schizophrenia. The mechanism by which
maternal influenza increases the risk of schizophrenia in the unborn baby is not
established. It is possible it is mediated through maternal antibodies to influenzae
cross-reacting with neuronal proteins, a mechanism that has been observed in rabbits
(122) or that certain mothers are genetically predisposed to produce a harmful
immune response (123) Any theory attempting to explain this association must also
account for why only a minority of mothers infected with influenzae during
pregnancy have a child who becomes schizophrenic.

Several studies have found that obstetric complications during antenatal life or
delivery are more frequent in patients with schizophrenia, especially in male, early
onset schizophrenics. (124-133) However, a meta-analysis of such studies suggests
that there may be considerable publication bias in the literature and that prospective,
population based studies tended to be largely negative. (134) Acute late onset and
female schizophrenic subjects do not seem to share the excess of obstetric
complications which may be one reason why not all studies show such an
association. (135-137) Ischaemia is the mechanism by which obstetric complications
have been proposed to increase the risk of the later development of schizophrenia.
Obstetric complications causing hypoxic ischaemia in the pre- or perinatal period
can lead to intraventricular or periventricular bleeds, resulting in ventricular
enlargement. (138) Furthermore, the pyramidal cells in the CA1 region of the
hippocampus are among the most vulnerable in the human brain to mild ischaemia.
Excitotoxic damage associated with perinatal hypoxia could also account for some of
the neurochemical abnormalities that are found in schizophrenia. (139) However,
pre-existing brain dysfunction may predispose to obstetrical complications and some
investigators have interpreted the association between obstetric complications and
schizophrenia as being an indication of fetal abnormality. (140)

Maternal malnutrition in early gestation (141, 142) is another intrauterine
environmental event which appears to increase the risk of developing schizophrenia
in a dose dependent way. However, this study (142) did not control for the
implication of social class both in access to food and on risk for schizophrenia.
Nevertheless, four lines of evidence support prenatal nutritional deficiencies as a
plausible set of risk factors for schizophrenia: (143)

Their effects are not incompatible with the epidemiology of schizophrenia

They have adverse effects on brain development

General malnutrition results in neuropathological anomalies of brain regions
implicated in schizophrenia

In the light of the widely accepted data that genetic factors convey susceptibility to
schizophrenia, it is not surprising that there have been speculation about genetic
factors that may affect brain development in schizophrenia. Since approximately
30% of the genome is expressed in the brain (144) and many genes are turned on and
off during discrete phases of brain development, there are many potential candidate
genes for aberrant neurodevelopment. It is suggested a mutation in a gene relating to
brain development could result in the neuropathological deviations found in the
developing brain. (145) Alternatively, it is hypothesized a genetic defect could
predispose the schizophrenic brain to be adversely affected by intrauterine or
perinatal environmental events. Another possibility is that the genetic control of
brain development may be disrupted by adverse environmental events which results
in the cerebral pathologies found in the brains of schizophrenics. (146)

It is easy to see how the neuronal abnormalities in the frontal and temporal lobes
could result in an abnormal pattern of cortical connections and cause the premorbid
abnormalities in children and the social and cognitive defects shown by
schizophrenic adults. However, the neurodevelopmental hypothesis proposes that
such pre or perinatal lesions can produce the positive symptoms of schizophrenia 2-3
decades later.

Animal studies have demonstrated that a brain lesion sustained in early life can
remain quiescent until early adulthood after which time in influences behavioural and
neuropharmacological phenomena that mimic schizophrenia. For example, neonatal
damage in the temporal lobe has little effect in juvenile monkeys, but leads to
behavioural and pharmacological abnormalities in adulthood. (147) Also, prenatal
lesions in the hippocampi of rats remain apparently silent until adult life. (148-154)
Nevertheless, although these studies do show that a defect in development can result
in a latency before the onset of symptoms they do not demonstrate spontaneous late
deterioration of function after an early lesion which is what occurs in schizophrenia.
A study in monkeys have been interpreted as showing that prenatal lesions of the
dorsolateral prefrontal cortex can remain undetected until sexual maturity when
deficits in neuropsychological tests arise. (155) However, careful examination of the
study does not support this interpretation; the performance of the 'lesioned' monkeys
in the tests did not become poorer as they progressed from infancy into adulthood,
the 'non-lesioned' monkeys just performed better. It should also be noted that the
performance of monkeys who sustained lesions in infancy was always superior to
those who sustained lesions in the juvenile period which is implies some degree of
compensatory organization. So therefore this study, although frequently cited as
supporting the neurobiological plausibility of the neurodevelopmental hypothesis, in
fact it does not.

It is possible that a similar process as is occurring in these animals with early brain
lesions explains why preschizophrenic children do not show the positive symptoms
of schizophrenia until early adult life. (156)

A large proportion of all the cells generated in the developing nervous system die by
the time it is mature. After peaking during childhood, synaptic density in the human
frontal cortex declines by 30-40% by adulthood. A process of selective neuronal
death and progressive synaptic elimination appears to operate throughout
adolescence to eliminate early errors of connection and it is suggested that this
sculpting of this nervous system might be abnormal in schizophrenia. (157-160)
Integrating this idea with the neurodevelopmental hypothesis results in the
suggestion that the maldevelopment in utero sets the stage for secondary synaptic
disorganisation in adolescence. This hypothesis has been supported by: phosphorus-
31 magnetic resonance spectroscopy studies of neural membrane phospholipid
turnover. (161, 162)

Alternatively it is possible that lesion remains dormant until the normal processes of
brain maturation in adolescence lead to the use of neuronal circuits that are not
greatly developed in children. In support of this idea it has been found that in
humans the development (myelination) of circuitry to and from the hippocampus is
only complete in adolescence, providing a mechanism whereby a lesion affecting this
area may not be apparent until these pathways are mature. (168) Also proposed have
been the possibilities of abnormalities of neuronal sprouting (169) or adverse effects
of stress related neural transmission. (165)

Finally, support for the neurobiological plausibility of the latency period in
schizophrenia comes from studying human developmental disorders which also
exhibit this phenomenon. Both temporal lobe epilepsy and metachromatic
leukodystrophy provide a 'mock-up' of schizophrenia. (166, 167)

In summary, there is substantial amount of evidence in support of a
neurodevelopmental basis for schizophrenia. A specific aetiology is not implicated
and multiple genetic and environmental factors may be relevant. These causal
factors interact, in an unknown way, to produce aberrant fetal development. It is not
certain whether this early developmental aberration is necessary and/or sufficient to
'cause' schizophrenia; probably it just leaves the individual susceptible to the
disorder. If, and when the symptoms of schizophrenia occur is thought to be
determined by the intervening processes of postnatal cerebral maturation.

In order to advance the understanding of the aetiology of schizophrenia future
research needs to concentrate on furthering the understanding of brain development
and maturation. The genes, proteins and molecular mechanisms involved in normal
neuronal proliferation, migration and synapse formation need to be determined.
Hopefully, this knowledge will enable the mechanisms involved in aberrant
neurodevelopment to be understood. Studies are needed to define the peripubertal
trigger which causes the development of psychotic symptoms and explain how and
why the disease remains latent for 20-30 years Another area warranting further study
is the interactions between the genes and environmental factors associated with the
development of schizophrenia.

Few of the positive findings supporting the neurodevelopmental hypothesis are
undisputed. These inconsistencies probably reflect the fact that schizophrenia is
actually a group of pathogenically diverse disorders, of which only one has a
neurodevelopmental origin. Indeed, this possibility seems likely because of the
clinical diversity of schizophrenia and the many examples elsewhere in medicine
where complex phenotypes turn out to be aggregates of discrete diseases. To date,
however, attempts to subdivide schizophrenia have yet to provide any evidence of
heterogenicity at the neurodevelopmental, or any other, pathogenetic level.